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Biomedical subjects

K A Martin

Publications and source records attributed to K A Martin.

At least 19 recordsLinked to original sources
PubMed2006

Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways.

Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), inhibits tumor cell motility. However, the underlying mechanism is poorly understood. Here, we show that rapamycin inhibited type I insulin-like growth factor (IGF-I)-stimulated motility of a panel of cell lines. Expression of a rapamycin-resistant mutant of mTOR (mTORrr) prevented rapamycin inhibition of cell motility. However, cells expressing a kinase-dead mTORrr remained sensitive to rapamycin. Downregulation of raptor or rictor by RNA interference (RNAi) decreased cell motility. However, only downregulation of raptor mimicked the effect of rapamycin, inhibiting phosphorylation of S6 kinase 1 (S6K1) and 4E-BP1. Cells infected with an adenovirus expressing constitutively active and rapamycin-resistant mutant of p70 S6K1, but not with an adenovirus expressing wild-type S6K1, or a control virus, conferred to resistance to rapamycin. Further, IGF-I failed to stimulate motility of the cells, in which S6K1 was downregulated by RNAi. Moreover, downregulation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) by RNAi-attenuated rapamycin inhibition of cell motility. In contrast, expression of constitutively active 4E-BP1 dramatically inhibited IGF-I-stimulated cell motility. The results indicate that both S6K1 and 4E-BP1 pathways, regulated by TORC1, are required for cell motility. Rapamycin inhibits IGF-I-stimulated cell motility, through suppression of both S6K1 and 4E-BP1/eIF4E-signaling pathways, as a consequence of inhibition of mTOR kinase activity.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Long-term exercise training in persons with spinal cord injury: effects on strength, arm ergometry performance and psychological well-being.

STUDY DESIGN: Randomized controlled trial of exercise training in persons with spinal cord injury. OBJECTIVE: The purpose of this study was to examine the effects of 9 months of twice-weekly exercise training on strength, arm ergometry performance, and indices of psychological well-being and quality of life. SETTING: Centre for Health Promotion and Rehabilitation, McMaster University, Hamilton, Ontario, Canada. METHODS: Thirty-four men and women (aged 19-65 years) with traumatic spinal cord injury (C4-L1; ASIA A-D) of 1-24 years duration volunteered to participate, and were randomized into exercise (EX; n=21) and control (CON; n=13) groups. Twenty-three subjects (11 EX; 12 CON) successfully completed the 9-month study. Subjects were assessed for one repetition maximum (1RM) strength, arm ergometry performance, and several indices of quality of life and psychological well-being at baseline, 3, 6, and 9 months. RESULTS: At baseline, there were no significant differences between groups in age, submaximal arm ergometry performance, muscle strength, or psychological well-being. Following training, the EX group had significant increases in submaximal arm ergometry power output (81%; P<0.05), and significant increases in upper body muscle strength (19-34%; P<0.05); no significant changes occurred in CON. Participants in EX reported significantly less pain, stress and depression after training, and scored higher than CON in indices of satisfaction with physical function, level of perceived health and overall quality of life (P<0.05). Exercise adherence (per cent of prescribed sessions attended) in those subjects who completed the 9 months of training was 82.5%. CONCLUSIONS: These results demonstrate that long-term twice-weekly exercise training in this population is feasible, and results in significant gains in both physical and psychological well-being.

Adult↗
PubMed2001

Point-of-purchase messages framed in terms of cost, convenience, taste, and energy improve healthful snack selection in a college foodservice setting.

OBJECTIVE: To examine the effects of a point-of-purchase (POP) intervention emphasizing various properties of healthful food items on college students' snack purchases. DESIGN: In Study 1, vegetable baskets (containing cut pieces of vegetables), fruit baskets (containing cut pieces of fruit), pretzels, and yogurt were promoted in separate POP interventions. Food sales were monitored over 2-week baseline, 4-week intervention, and 2-week follow-up periods. In Study 2, yogurt was promoted across a 2-week baseline, 12-week intervention, and 2-week follow-up periods and an intercept survey was conducted. SUBJECTS/SETTING: Approximately 2,280 university students were potentially exposed to the intervention, and 72 students responded to the intercept survey. INTERVENTION: POP messages were placed on an 11 x 17-in poster located at the cafeteria entrance, and two 4 x 2.5-in signs placed next to the targeted food item. Messages emphasized the Budget-friendly, Energizing, Sensory/taste, Time efficient/convenient (BEST) stimulus properties of food. MAIN OUTCOME MEASURES: Daily sales of the targeted food items. STATISTICAL ANALYSES PERFORMED: Analyses of variance with Tukey post hoc tests were used to compare food sales during the baseline, intervention, and follow-up periods. RESULTS: In Study 1, yogurt and pretzel sales increased during the intervention and post-intervention periods (P<.05). Interventions had no effect on fruit basket and vegetable basket sales (P>.05), but whole fruit sales increased during the fruit basket intervention and follow-up (P<.05). In Study 2, yogurt sales were significantly greater during the intervention and follow-up periods than at baseline (P<.01). APPLICATIONS/CONCLUSIONS: Using the BEST properties in POP interventions may be beneficial in promoting the consumption of healthful foods among university students, particularly when the targeted foods are priced comparably to less healthful foods.

Canada↗
PubMed2001

Serum and follicular fluid hormone levels during in vitro fertilization after short- or long-course treatment with a gonadotropin-releasing hormone agonist.

OBJECTIVE: To examine the impact of flare (short) vs. down-regulation (long) GnRH agonist (GnRH-a) on serum and follicular fluid (FF) LH and androgen concentrations in women undergoing IVF treatment cycles. DESIGN: Prospective observational study. SETTING: IVF clinic. PATIENT(S): One hundred sixteen ovulatory subjects undergoing IVF. INTERVENTION(S): Fifty-eight ovulatory patients undergoing a down-regulation regimen matched with 58 undergoing the flare regimen as part of an IVF cycle. MAIN OUTCOME MEASURE(S): Serum concentrations of LH, FSH, Progesterone (P4), Androstenedione (A), T, and E(2) on the day of hCG administration were compared between the two groups. In addition, the FF P4, 17OHP4, A, T, and E(2) levels were compared in the two groups. RESULT(S): Serum LH was significantly higher with the flare regimen (15.2 +/- 1.14 IU/L, P<.05) when compared with results with the down-regulation protocol (9.5 +/- 0.77 IU/L). In addition, FF A was significantly higher in the flare protocol (57.3 +/- 13.3 ng/mL, P<.05) compared with in the down-regulation protocol (27 +/- 2.44 ng/mL). Serum and FF P4, 17OH P4, T, and E(2) were not statistically significantly different between the two groups. CONCLUSION(S): Serum LH and FF A are significantly higher in the flare regimen in comparison with the down-regulation regimen. Circulating LH appears to play a role in determining FF A concentration.

Adult↗
PubMed2001

Role of self-presentation in the health practices of a sample of Irish adolescents.

The association between self-presentational motives and health behaviors were studied in a sample of 183 Irish adolescents. Among girls, dieters and nonexercisers scored higher on measures of trait self-presentational concern than nondieters and exercisers. Self-presentational concerns were positively correlated with boys' and girls' endorsement of self-presentational motives for certain health practices.

Adolescent↗
PubMed2001

Does bouton morphology optimize axon length?

The total length of cortical axons could be reduced if the parent axons maintained straight trajectories and simply connected to dendritic shafts via spine-like terminaux boutons and to dendritic spines via bead-like en passant boutons. Cortical axons from cat area 17 were reconstructed from serial electron micrographs and their bouton morphology was correlated with their synaptic targets. En passant or terminaux boutons did not differ in the proportion of synapses they formed with dendritic spines and shafts, and thus, the two morphological variants of synaptic bouton do not contribute directly to optimizing axon length.

Animals↗
PubMed2001

Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea.

BACKGROUND: Hypothalamic amenorrhoea (HA) is a syndrome associated with infertility and osteopenia in reproductive-age women. METHODS: To understand better the natural history of this disorder, 28 women participated in a retrospective, questionnaire-based analysis to elucidate factors associated with spontaneous recovery. RESULTS: 54% of subjects developed HA related to an eating disorder, 21% related to stress +/- weight loss, and 25% without obvious contributing factors (idiopathic). HA associated with a clear precipitant had a better prognosis than idiopathic HA (71 versus 29% recovery; P < 0.05). Reversal of the inciting factor appeared necessary but not sufficient for recovery (83% recovery if factor reversed). Normal menarche occurred in 61% of subjects, oligomenorrhoea in 32%, and primary amenorrhoea in 7%. Oligomenorrhoea and normal menarche showed a trend toward better prognosis than primary amenorrhoea (NS). Compared with controls, 46% of HA patients had decreased frequency of LH pulses, 7% decreased amplitude, 18% decreases in both frequency and amplitude, 18% absent pulses, and 11% normal-appearing pulses. Pulse pattern at baseline did not predict recovery. CONCLUSIONS: The aetiology of HA at the time of presentation predicts subsequent recovery of menstrual function. In stress, weight loss, or eating disorder-related HA, rates of recovery exceeded 80% when precipitating factors were reversed. Idiopathic HA may represent a different disorder as recovery rates were <30%.

Adolescent↗
PubMed2001

Prevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadism.

Mutations in the GnRH receptor (GNRHR) have been described as a cause of reproductive failure in a subset of patients with idiopathic hypogonadotropic hypogonadism (IHH). Given the apparent rarity of these mutations, we set out to determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with IHH who were well characterized with respect to diagnosis, phenotype, and mode of inheritance and to define their distribution within the receptor protein. One hundred and eight probands with IHH were screened for mutations in the coding sequence of GNRHR. Forty-eight of the 108 patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia (Kallmann syndrome). Exon segments in the GNRHR were screened for mutations using temperature gradient gel electrophoresis, and all mutations were confirmed by direct sequencing. Five unrelated probands (3 men and 2 women), all normosmic, were documented to have changes in the coding sequence of the GNRHR. Two of these probands were from a subgroup of 5 kindreds consistent with a recessive mode of inheritance, establishing a GNRHR mutation frequency of 2 of 5 (40%) in patients with normosmic, autosomal recessive IHH. The remaining 3 probands with GNRHR mutations were from a subgroup of 18 patients without evidence of familial involvement, indicating a prevalence of 3 of 18 (16.7%) in patients with sporadic IHH and a normal sense of smell. Among the five individuals bearing GNRHR mutations, a broad spectrum of phenotypes was noted, including testicular sizes in the male that varied from prepubertal to the normal adult male range. Three probands had compound heterozygous mutations, and two had homozygous mutations. Of the eight DNA sequence changes identified, four were novel: Thr(32)Ile, Cys(200)Tyr, Leu(266)Arg, and Cys(279)TYR: COS-7 cells transiently transfected with complementary DNAs encoding the human GNRHR containing each of these four novel mutations failed to respond to GnRH agonist stimulation. We conclude that 1) the spectrum of phenotypes in patients with GNRHR mutations is much broader than originally anticipated; 2) the frequency of GNRHR mutations may be more common than previously appreciated in familial cases of normosmic IHH and infrequent in sporadic cases; and 3) functional mutations of the GNRHR are distributed widely throughout the protein.

Amino Acid Sequence↗
PubMed2001

Specific factors predict the response to pulsatile gonadotropin-releasing hormone therapy in polycystic ovarian syndrome.

Ovulation induction is particularly challenging in patients with polycystic ovarian syndrome (PCOS) and may be complicated by multifollicular development. Pulsatile GnRH stimulates monofollicular development in women with anovulatory infertility; however, ovulation rates are considerably lower in the subgroup of patients with PCOS. The aim of this retrospective study was to determine specific hormonal, metabolic, and ovarian morphological characteristics that predict an ovulatory response to pulsatile GnRH therapy in patients with PCOS. Subjects with PCOS were defined by chronic amenorrhea or oligomenorrhea and clinical and/or biochemical hyperandrogenism in the absence of an adrenal or pituitary disorder. At baseline, gonadotropin dynamics were assessed by 10-min blood sampling, insulin resistance by fasting insulin levels, ovarian morphology by transvaginal ultrasound, and androgen production by total testosterone levels. Intravenous pulsatile GnRH was then administered. During GnRH stimulation, daily blood samples were analyzed for gonadotropins, estradiol (E(2)), progesterone, inhibin B, and androgen levels, and serial ultrasounds were performed. Forty-one women with PCOS underwent a total of 144 ovulation induction cycles with pulsatile GnRH. Fifty-six percent of patients ovulated with 40% of ovulatory patients achieving pregnancy. Among the baseline characteristics, ovulatory cycles were associated with lower body mass index (P < 0.05), lower fasting insulin (P = 0.02), lower 17-hydroxyprogesterone and testosterone responses to hCG (P < 0.03) and higher FSH (P < 0.05). In the first week of pulsatile GnRH treatment, E(2) and the size of the largest follicle were higher (P < 0.03), whereas androstenedione was lower (P < 0.01) in ovulatory compared with anovulatory patients. Estradiol levels of 230 pg/mL (844 pmol/L) or more and androstenedione levels of 2.5 ng/mL (8.7 nmol/L) or less on day 4 and follicle diameter of 11 mm or more by day 7 of pulsatile GnRH treatment had positive predictive values for ovulation of 86.4%, 88.4%, and 99.6%, respectively. Ovulatory patients who conceived had lower free testosterone levels at baseline (P < 0.04). In conclusion, pulsatile GnRH is an effective and safe method of ovulation induction in a subset of patients with PCOS. Patient characteristics associated with successful ovulation in response to pulsatile GnRH include lower body mass index and fasting insulin levels, lower androgen response to hCG, and higher baseline FSH. In ovulatory patients, high free testosterone is negatively associated with pregnancy. A trial of pulsatile GnRH therapy may be useful in all PCOS patients, as E(2) and androstenedione levels on day 4 or follicle diameter on day 7 of therapy are highly predictive of the ovulatory response in this group of patients.

Adult↗
PubMed2000

Regulation of ribosomal S6 kinase 2 by effectors of the phosphoinositide 3-kinase pathway.

Ribosomal S6 kinase (S6K1), through phosphorylation of the 40 S ribosomal protein S6 and regulation of 5'-terminal oligopyrimidine tract mRNAs, is an important regulator of cellular translational capacity. S6K1 has also been implicated in regulation of cell size. We have recently identified S6K2, a homolog of S6K1, which phosphorylates S6 in vitro and is regulated by the phosphatidylinositide 3-kinase (PI3-K) and mammalian target of rapamycin pathways in vivo. Here, we characterize S6K2 regulation by PI3-K signaling intermediates and compare its regulation to that of S6K1. We report that S6K2 is activated similarly to S6K1 by the PI3-K effectors phosphoinositide-dependent kinase 1, Cdc42, Rac, and protein kinase Czeta but that S6K2 is more sensitive to basal activation by myristoylated protein kinase Czeta than is S6K1. The C-terminal sequence of S6K2 is divergent from that of S6K1. We find that the S6K2 C terminus plays a greater role in S6K2 regulation than does the S6K1 C terminus by functioning as a potent inhibitor of activation by various agonists. Removal of the S6K2 C terminus results in an enzyme that is hypersensitive to agonist-dependent activation. These data suggest that S6K1 and S6K2 are similarly activated by PI3-K effectors but that sequences unique to S6K2 contribute to stronger inhibition of its kinase activity. Understanding the regulation of the two S6K homologs may provide insight into the physiological roles of these kinases.

Cells, Cultured↗
PubMed2000

Ribosomal S6 kinase 2 inhibition by a potent C-terminal repressor domain is relieved by mitogen-activated protein-extracellular signal-regulated kinase kinase-regulated phosphorylation.

Ribosomal S6 kinase 2 (S6K2) is a recently identified serine/threonine protein kinase that phosphorylates the 40 S ribosomal protein S6 in vitro. S6K2 is highly homologous to S6K1 in the core kinase and linker regulatory domains but differs from S6K1 in the N- and C-terminal regions and is differently localized primarily to the nucleus because of a C-terminal nuclear localization signal unique to S6K2. We have recently demonstrated that S6K2 is regulated similarly to S6K1 by the mammalian target of rapamycin pathway and by multiple PI3-K pathway effectors in vivo. However, deletion of the C-terminal domain of S6K2 enhances kinase activity, whereas analogous deletion of S6K1 is inhibitory. Here, we characterize the S6K2 C-terminal motifs that confer this differential regulation. We demonstrate that the inhibitory effects of the S6K2 C-terminal domain are only partly attributable to the nuclear localization signal but that three C-terminal proline-directed potential mitogen-activated protein kinase phosphorylation sites are critical mediators of this inhibitory effect. Site-specific mutation of these sites to alanine completely desensitizes S6K2 to activating inputs, whereas mutation to aspartic acid to mimic phosphorylation results in an activated enzyme which is hypersensitive to activating inputs. Pretreatment of cells with the mitogen-activated protein-extracellular signal-regulated kinase kinase (MEK) inhibitor U0126 inhibited S6K2 activation to a greater extent than S6K1. Furthermore, S6K2 mutants with C-terminal deletion or acidic phosphorylation site mutations displayed greatly reduced U0126 sensitivity. Thus, MEK-dependent inputs to C-terminal phosphorylation sites appear to be essential for relief of S6K2 inhibition but less critical for activation of S6K1. These data suggest a mechanism by which weak PI3-K agonists can regulate S6 phosphorylation and selective translation in the presence of mitogen-activated protein kinase signaling.

Butadienes↗
PubMed2000

Termination of the geniculocortical projection in the striate cortex of macaque monkey: a quantitative immunoelectron microscopic study.

The goal of this present study was to derive a new estimate of the synaptic contribution of the dorsal lateral geniculate nucleus (dLGN) to the subdivisions of its main recipient layer, layer 4C, of striate cortex of macaque monkey. The projection from the dLGN and its terminal boutons within layer 4C were visualized by immunodetection of the calcium binding protein, parvalbumin (PV), which is expressed in relay cells of the dLGN. The proportion of asymmetric synapses formed by PV-positive boutons within the alpha and beta sublayers of 4C was estimated by using a nonbiased stereological counting method. The proportion of asymmetric synapses contributed by the PV-positive boutons to layer 4Calpha is 8.7%; to 4Cbeta is 6.9%. Assuming all the PV-positive asymmetric synapses derive from the dLGN relay cells, this gives a ratio of dLGN synapses per neuron of 192 in layer 4Calpha and 128 in layer 4Cbeta. Thus, the recurrent excitatory input from neighboring cortical neurons must play an important part in responses of the neurons lying at the input stage of the cortical circuit.

Animals↗
PubMed2000

Ultrasonographic detection of orbicularis oris defects in first degree relatives of isolated cleft lip patients.

The phenotypic variability of non-syndromic cleft lip (CL) is broad. We demonstrate that the prevalence of orbicularis oris (OO) muscle anomalies, detectable only by ultrasound, is higher in first-degree relatives of individuals with overt CL than in the general population. These findings suggest that occult OO defects may be part of the spectrum of the CL phenotype, that offspring of individuals with such defects are at an increased risk to develop overt CL, and that ultrasound may be a useful tool in future population studies designed to identify CL susceptibility genes.

Child↗
PubMed2000

The relationship between evaluative concerns and sport competition state anxiety among youth skiers.

Thirty-four youth competitive skiers (mean age = 13.74 years) completed measures of social evaluative concern and competitive anxiety. Consistent with past research, regression analyses showed that cognitive anxiety was related to performance-specific evaluative concerns. However, contrary to current conceptualizations of sport competition anxiety, somatic anxiety was correlated with concerns about evaluation of other non-performance aspects of ski racing. Competitive skiers were most concerned about parents' and friends' evaluations of their performance, and other competitors' and friends' evaluations of their skiing in general. These findings are discussed in relation to the theory and management of sport competition state anxiety.

Adolescent↗
PubMed2000

Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations.

GnRH receptor mutations have recently been identified in a small number of familial cases of nonanosmic hypogonadotropic hypogonadism. In the present report we studied a kindred in which two sisters with primary amenorrhea were affected with GnRH deficiency due to a compound heterozygote mutation (Gln(106)Arg, Arg(262)Gln) and performed extensive phenotyping studies. Baseline patterns of gonadotropin secretion and gonadotropin responsiveness to exogenous pulsatile GnRH were examined in the proband. Low amplitude pulses of both LH and free alpha-subunit (FAS) were detected during 24 h of every 10 min blood sampling. The proband then received exogenous pulsatile GnRH i.v. for ovulation induction, and daily blood samples for gonadotropins and sex steroids were monitored. At the conventional GnRH replacement dose for women with hypogonadotropic hypogonadism (75 ng/kg), no follicular development occurred. At a GnRH dose of 100 ng/kg, the level and pattern of gonadotropin secretion more closely mimicked the follicular phase of normal women; a single dominant follicle was recruited, and an endogenous LH surge was elicited. However, the luteal phase was inadequate, as assessed by progesterone levels. At a GnRH dose of 250 ng/kg, the gonadotropin and sex steroid dynamics reproduced those of normal ovulatory women in both the follicular and luteal phases, and the proband conceived. The FAS responses to both conventional and high dose GnRH were within the normal range. The following conclusions were made: 1) Increased doses of GnRH may be used effectively for ovulation induction in some patients with GnRH receptor mutations. 2) Higher doses of GnRH are required for normal luteal phase dynamics than for normal follicular phase function. 3) Hypersecretion of FAS in response to exogenous GnRH, which is a feature of congenital hypogonadotropic hypogonadism, was not seen in this patient with a GnRH receptor mutation.

Adolescent↗